Mycotoxins and Birth Defects: A Global Health Concern?

性状（由申请方提供）：伏马菌素B1（FB 1）是一种真菌毒素，由玉米的常见真菌污染物产生。最近，在依赖玉米作为主食的全球社区中，怀孕早期摄入FB 1污染的食物与后代患神经管缺陷（NTD）的风险增加有关。FB 1干扰从头鞘脂的生物合成，但确切的生化变化，有助于异常形态发生是未知的。该研究计划的目标是确定预测与胎儿畸形风险增加相关的FB 1暴露的生物化学和遗传生物标志物。在危地马拉，玉米中FB 1的发生是有据可查的，NTD的发生率通常是这种出生缺陷全球平均水平的6-10倍。已经进行了初步的接触评估，并确定了玉米中FB 1含量经常很高的特定社区。这项拟议的研究将利用从小鼠研究中获得的信息，评估和验证从已知食用大量FB 1污染玉米的女性中收集的人体样本中的生物标志物。该项目涉及克雷顿大学、杜克大学、USDA-ARS和危地马拉CIENSA的调查人员之间的合作努力。危地马拉的妇女将被要求填写旨在确定玉米消费量高和低的问卷，登记的受试者将提供尿液和血液斑点以供进一步分析。将在小鼠中进行平行暴露研究，以确定FB 1诱导的血液中鞘脂代谢物变化的剂量反应阈值。小鼠模型也将用于鉴定母体血液和胚胎神经组织中与NTD风险增加相对应的特定鞘脂代谢物，这些生物标志物将在从暴露于高和低水平FB 1的玉米消费者获得的人血斑中进行评估。此外，小鼠模型将用于进一步研究导致神经管闭合失败的潜在信号传导机制。其他研究将集中在发现和验证预测易感性增加的鞘脂途径基因的基因表达谱和基因突变。将根据小鼠鞘脂基因表达谱的qPCR分析选择用于人样本分析的候选基因。将筛选鞘脂代谢和信号传导途径中的基因，以确定人血斑和来自敏感与耐药小鼠品系的血斑中的突变。来自拟议研究的信息将构成前瞻性和回顾性流行病学研究的基础，以确定在以玉米为基础的文化中NTD的高风险妇女。此外，基于机制的生物标志物将提供一个关键的，目前缺乏的，风险评估的研究工具，并在制定战略，以减少NTD的发病率在全球社区的FB 1污染的玉米消费是频繁的援助。 伏马菌素（FB 1）是一种真菌毒素，由玉米中常见的真菌污染物产生。最近观察到在怀孕早期摄入FB 1污染的玉米与患有神经管缺陷（NTD）的孩子的风险增加之间存在关联。该应用程序的目的是确定尿液中FB 1暴露的生物标志物，以及与胎儿畸形风险增加唯一相关的血斑中的生物化学和遗传生物标志物。FB 1暴露数据、尿液和血斑将从危地马拉的玉米消费者受试者中收集。在对FB 1诱导的NTD敏感或耐药的小鼠模型中进行的机制研究将能够鉴定鞘脂代谢产物、基因表达谱和导致风险增加的基因突变。目标是发现和验证可用于预测人类风险的生物标志物，以便我们可以预防和/或减少严重依赖玉米作为膳食主食的全球人群中NTD的发生率。

DESCRIPTION (provided by applicant): Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of corn. Ingestion of FB1-contaminated food during early pregnancy has recently been linked to increased risk for offspring with neural tube defects (NTDs) in global communities that rely on maize as a dietary staple. FB1 interferes with de novo sphingolipid biosynthesis, but the exact biochemical changes that contribute to abnormal morphogenesis are unknown. The objectives of the research plan are to identify biochemical and genetic biomarkers that predict FB1 exposures associated with increased risk for fetal malformations. In Guatemala, the occurrence of FB1 in maize is well documented, and the incidence of NTDs is often 6-10 times the global average for this type of birth defect. Preliminary exposure assessments have been conducted, and specific communities have been identified where FB1 in maize is frequently high. The proposed research will use information obtained from mouse studies to assess and validate biomarkers in human samples collected from women known to consume large amounts of FB1-contaminated maize. The project involves a collaborative effort between investigators at Creighton University, Duke University, USDA-ARS and CIENSA in Guatemala. Women in Guatemala will be asked to complete questionnaires intended to identify high and low consumers of maize, and enrolled subjects will provide urine and blood spots for further analysis. Parallel exposure studies will be done in mice in order to determine the dose-response threshold for FB1-induced alterations in sphingolipid metabolites in blood. Mouse models will also be used to identify the specific sphingolipid metabolites in maternal blood and embryonic neural tissue that correspond to increased risk for NTDs, and these biomarkers will be evaluated in human blood spots obtained from maize consumers exposed to high and low levels of FB1. In addition, mouse models will be used to further investigate the underlying signaling mechanisms involved that result in failure of neural tube closure. Additional studies will focus on the discovery and validation of gene expression profiles and genetic mutations in sphingolipid pathway genes that predict increased susceptibility. Candidate genes for analysis in human samples will be selected based on qPCR analyses of sphingolipid gene expression profiles in mice. Genes in sphingolipid metabolism and signaling pathways will be screened for mutations in human blood spots and in blood spots from susceptible vs. resistant mouse strains. Information from the proposed studies will form the basis for prospective and retrospective epidemiological studies to identify women at high risk for NTDs in maize-based cultures. In addition, mechanism-based biomarkers will provide a critical, and currently lacking, research tool for risk assessment, and aid in developing strategies for reducing the incidence of NTDs in global communities where consumption of FB1-contaminated maize is frequent. PUBLIC HEALTH RELEVANCE: Fumonisin (FB1) is a mycotoxin produced by a common fungal contaminant of maize. An association has recently been observed between ingestion of FB1-contaminated maize during early pregnancy and increased risk for having a child with a neural tube defect (NTD). The purpose of the application is to identify biomarkers of FB1 exposure in urine, and biochemical and genetic biomarkers in blood spots that are uniquely linked to increased risk for fetal malformations. FB1 exposure data, urine, and blood spots will be collected from human subjects in Guatemala who are consumers of maize. Mechanistic studies in mouse models that are susceptible or resistant to FB1-induced NTDs will enable the identification of sphingolipid metabolites, gene expression profiles, and genetic mutations that confer increased risk. The goal is the discovery and validation of biomarkers that can be used to predict risk in humans, such that we can prevent and/or reduce the incidence of NTDs in global populations that rely heavily on maize as a dietary staple.